A surprising variety of ion channels found in a wide range of species from Homo to Paramecium use calmodulin (CaM) as their constitutive or dissociable Ca(2+)-sensing subunits. The list includes voltage-gated Ca(2+) channels, various Ca(2+)- or ligand-gated channels, Trp family channels, and even the Ca(2+)-induced Ca(2+) release channels from organelles. Our understanding of CaM chemistry and its relation to enzymes has been instructive in channel research, yet the intense study of CaM regulation of ion channels has also revealed unexpected CaM chemistry. The findings on CaM channel interactions have indicated the existence of secondary interaction sites in addition to the primary CaM-binding peptides and the functional differences between the N- and C-lobes of CaM. The study of CaM in channel biology will figure into our understanding on how this uniform, universal, vital, and ubiquitous Ca(2+) decoder coordinates the myriad local and global cell physiological transients.